title: ONO-8130, a selective prostanoid EP1 receptor antagonist, relieves bladder pain in mice with cyclophosphamide-induced cystitis.
abstract: Given the previous evidence for involvement of prostanoid EP1 receptors in facilitation of the bladder afferent nerve activity and micturition reflex, the present study investigated the effect of ONO-8130, a selective EP1 receptor antagonist, on cystitis-related bladder pain in mice. Cystitis in mice was produced by intraperitoneal administration of cyclophosphamide at 300mg/kg. Bladder pain-like nociceptive behavior and referred hyperalgesia were assessed in conscious mice. Phosphorylation of extracellular signal-regulated kinase (ERK) in the L6 spinal cord was determined by immunohistochemistry in anesthetized mice. Cyclophosphamide treatment caused bladder pain-like nociceptive behavior and referred hyperalgesia accompanying cystitis symptoms, including increased bladder weight and vascular permeability and upregulation of cyclooxygenase-2 in the bladder tissue. Oral preadministration of ONO-8130 at 0.3-30 mg/kg strongly prevented both the bladder pain-like behavior and referred hyperalgesia in a dose-dependent manner, but had slight effect on the increased bladder weight and vascular permeability. Oral ONO-8130 at 30 mg/kg also reversed the established cystitis-related bladder pain. Intravesical administration of prostaglandin E2 caused prompt phosphorylation of ERK in the L6 spinal cord, an effect blocked by ONO-8130. Our findings strongly suggest that the prostaglandin E2/EP1 system participates in processing of cystitis-related bladder pain, and that EP1 antagonists including ONO-8130 are useful for treatment of bladder pain, particularly in interstitial cystitis. Prostaglandin E2 contributes to cystitis-related bladder pain via EP1 receptors in mice, indicating possible therapeutic usefulness of selective EP1 antagonists.
authors.affiliation: Division of Pharmacology and Pathophysiology, Kinki University School of Pharmacy, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan Pharmacological Research Laboratories, Ono Pharmaceutical Co, Ltd, Osaka 618-8585, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Miki
authors.forename: Maho
authors.initials: M
authors.lastname: Matsunami
authors.forename: Saori
authors.initials: S
authors.lastname: Nakamura
authors.forename: Hiroki
authors.initials: H
authors.lastname: Okada
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Matsuya
authors.forename: Atsufumi
authors.initials: A
authors.lastname: Kawabata
mesh_terms: D000284:Administration, Oral; D000818:Animals; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D003520:Cyclophosphamide / Q000009:adverse effects; D003556:Cystitis / Q000139:chemically induced / Q000150:complications*; D015232:Dinoprostone / Q000494:pharmacology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D010146:Pain / Q000150:complications / Q000188:drug therapy* / Q000209:etiology*; D010147:Pain Measurement; D012333:RNA, Messenger / Q000378:metabolism; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D001745:Urinary Bladder Diseases / Q000150:complications / Q000209:etiology* / Q000517:prevention & control*; D014746:Vimentin / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D058306:Receptors, Prostaglandin E, EP1 Subtype; D014746:Vimentin; D003520:Cyclophosphamide; D051546:Cyclooxygenase 2; D015232:Dinoprostone